Mycobacterium is a genus in the class of bacteria called Actinobacteria with its own distinct family known as Mycobacteriacae. Mycobacterium contains various obligate and opportunistic pathogens of animals, which may also be transmitted to humans and cause disease in humans, thus exhibiting a considerable zoonotic potential. During the past few decades, members of the Mycobacterium avium-intracellulare complex (MAIC) emerged as pathogens of human diseases, including lymphadenitis in children, pulmonary tuberculosis-like disease, and disseminated infections (occurring predominantly in immunocompromised persons, particularly AIDS patients). Similarly, important animal diseases result from infections in an animal by members of this group, e.g., avian tuberculosis and paratuberculosis in ruminants. MAIC includes M. intracellulare and 4 subspecies of M. avium, namely, M. avium subsp. avium, M. avium subsp. hominissuis, M. avium subsp. silvaticum, and M. avium subsp. paratuberculosis. Whereas members of the M. tuberculosis complex are transmitted by direct host contact, MAIC species are acquired predominantly from environmental sources, including soil, water, dust, and feed.
Mycobacterium tuberculosis (MTB) is a small aerobic non-motile high-GC bacillus with an “outer-membrane” that is unusually thick, “waxy,” hydrophobic, rich in mycolic acids, and extremely impermeable, making mycobacterium infections difficult to treat. One third of the world's population is thought to be infected (including latent MTB), but this number increases to upwards of 80% of the population in many Asian and African countries. If untreated, the death rate from active MTB infections is more than 50%. In addition, the combination of HIV and MTB is deadly and increasing numbers of MTB strains are becoming resistant to standard of care drugs; approximately 300,000 new cases of multidrug resistant (MDR) M. tuberculosis are reported each year. Multidrug resistant (MDR) M. tuberculosis are resistant to isoniazid and rifampicin, and extensive drug resistant (XDR) M. tuberculosis are also resistant to at least one quinolone and one aminoglycoside. As can be seen in FIG. 1, XDR M. tuberculosis has been reported across much of the globe.
Add to these issues the ease of transmission, as shown in FIG. 2, the globalization of travel, and the ongoing relocation and emigration of many segments of the world's population and it is apparent that MTB is becoming a global crisis.
Synthetic drugs for treating tuberculosis (TB) have been available for over half a century, but incidences of the disease continue to rise world-wide. More than 2 billion people are currently infected with M. tuberculosis, most being latent cases, and it is estimated that over 9 million new cases occur each year, worldwide, resulting in from 1.7 to nearly 2 million deaths per year. In 2004 alone approximately 24,500 new infections and close to 5,500 deaths were recorded, each day. See Zignol, M et al., M. Surveillance of anti-tuberculosis drug resistance in the world: an updated analysis, 2007-2010. Bull. World Health Organ 2012, 90 (2), 111-119D) Co-infection with HIV is driving the increase in incidence (Williams, B. G.; Dye, C. Science, 2003, 301, 1535) and the cause of death in 31% of AIDS patients in Africa can be attributed to TB. See Corbett, E. L et al., Arch. Intl. Med., 2003, 163, 1009, Septkowitz, A et al., Clin. Microbiol. Rev. 1995, 8, 180).
The limitations of tuberculosis therapy and prevention are well known. The current available vaccine, BCG was introduced in 1921 and fails to protect most people past childhood. According to a 2006 report—“International Standards for Tuberculosis Care”, a document developed by the Tuberculosis Coalition for Technical Assistance (TBCTA) which partners include Centers for Disease Control, American Thoracic Society, Tuberculosis Foundation, KNCV, the World Health Organization and the International Union Against Tuberculosis and Lung Disease—patients who do become infected with active disease currently endure two months of combination therapy with medicines introduced between 50 and 60 years ago—isoniazid (1952), rifampin (1963), pyrazinamide (1954) and ethambutol (1961)—followed by another 4 months of isoniazid and rifampin (also known as rifampicin). Alternatively the continuation phase could include Isoniazid and ethambutol for six months when adherence cannot be assessed, but according to this report, a longer continuation phase is associated with a higher rate of failure and relapse, especially in patients with HIV infection. Moreover, as detailed in this report, the doses of antituberculosis drugs used should conform to international recommendation and fixed-dose combinations of two (isoniazid and rifampicin), three (isoniazid, rifampicin, and pyrazinamide), and four (isoniazid, rifampicin, pyrazinamide, and ethambutol) drugs are highly recommended, especially when it is not possible to monitor the patient to ensure the treatment is ingested.
Daily dosing is required in these treatment phases and poor compliance drives the emergence and spread of multi-drug-resistant strains, which are challenging to treat. Shorter courses of more active agents which can be taken less frequently and which present a high barrier to the emergence of resistance, i.e. agents which are effective against multi-drug resistant strains of TB (MDR-TB), are urgently required. A March 2013 report (http://www.aidsmap.com/Once-weekly-continuation-phase-TB-treatment-equals-standard-of-care/page/2589498/) suggests that a two-drug combination of rifapentine (a long-acting derivative of rifampicin) with moxifloxacin (a fluoroquinolone antibiotic that has not been used previously in TB treatment) can allow tuberculosis (TB) treatment to be taken once-weekly during the four-month continuation phase and achieves the same standard of care as the traditional continuation treatment of daily treatment with isoniazid and rifampin. Such a treatment phase would allow treatment supervision to extend throughout the continuation phase, increasing adherence. However, moxifloxacin is not yet approved for treatment of TB, and the once-weekly treatment protocol is not yet endorsed or approved as an alternative standard of care treatment—guideline panels at international and national levels will need to review the published evidence to determine if this alternative continuation treatment protocol should be recommended and adopted. In addition, rifapentine is expensive, and interactions between rifapentine and antiretroviral drugs in the non-nucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitor classes may prevent its use in TB patients who are also HIV positive and taking antiretroviral medicines. Thus, at present, the costs/benefits analysis of a continuation treatment with weekly rifapentine versus daily rifampicin is yet to be fully assessed.
The tuberculosis drug Sirturo™ (bedaquiline) was approved in the United States in late December 2012, and another, delamanid, is attempting to gain regulatory approval in the EU. However, both are reserved for drug-resistant tuberculosis, which accounts for just 5% of new cases. A 2007 Editorial and News Focus in Nature Medicine discusses many aspects of TB such as pathogenesis, epidemiology, drug discovery and vaccine development to date (Nature Medicine, 2007, Focus on Tuberculosis, Vol 13(3), pages 263-312), noting that 125 years after the anniversary of the discovery of Mycobacterium tuberculosis, more than one-third of people in the world are infected with M. tuberculosis, and of these, more than 1 in 10 will develop the disease known as tuberculosis, formerly known as consumption, in their lifetime.
When coupled with the emergence of multi-drug resistant strains of Mycobacterium tuberculosis (MDR-TB), the scale of the problem is amplified. The global rise of bacteria and other microorganisms resistant to antibiotics and antimicrobials in general, poses a major threat. Deployment of massive quantities of antimicrobial agents into the ecosphere during the past 60 years has introduced a powerful selective pressure for the emergence and spread of antimicrobial-resistant pathogens. There is therefore a need to discover and develop new chemical entities to treat TB (recent leads are reviewed in: Grosset J H, Singer T G, Bishai W R. New Drugs for the Treatment of Tuberculosis: Hope and Reality. Int J Tuberc Lung Dis. 2012 August; 16(8):1005-14).
The present invention relates to certain substituted benzoxaboroles that show unexpected selectivity for inhibiting replication of Mycobacterium tuberculosis (M. tuberculosis) versus inhibition (toxicity) of human cells compared to other substituted benzoxaboroles, and exhibit sub-micromolar MIC values against mycobacterium species, particularly Mycobacterium tuberculosis and Mycobacterium tuberculosis complex (MTC), Mycobacterium avium and Mycobacterium avium complex (MAC) and Mycobacterium avium intracellulare complex (MAIC). Generally speaking, the benzoxaborole ring of substituted benzoxaborole has the following structure as shown below in Formula I, and may be characterized with the following substituent numbering system:
It is understood that the International Union of Pure and Applied Chemistry (IUPAC) nomenclature may designate a different numbering system depending on substituents around the benzoxaborole ring. Throughout this application, unless the IUPAC name is given for a specific compound, the substituted benzoxaboroles disclosed herein may be named and numbered using the numbering scheme depicted in Formula I, shown above.
Boron-containing molecules such as benzoxaboroles that are useful as antimicrobials have been described previously, see e.g. “Benzoxaboroles—Old compounds with new applications” Adamczyk-Woźniak, A. et al., Journal of Organometallic Chemistry Volume 694, Issue 22, 15 Oct. 2009, Pages 3533-3541, and U.S. Pat. Pubs. US20060234981, US20070155699, WO2012033858, and US2013165411.
Certain substituted benzoxaboroles which are substituted at position 7 may form a tricyclic benzoxaborole compound (see US20090227541, US2013165411 and WO/KR2015/016558). Applicants have surprisingly found that certain substituted benzoxaboroles substituted at the 7 position (numbered using the numbering scheme depicted in Formula I, shown above) may also exist as an equilibrium mixture of a tricyclic benzoxaborole structure and a bicyclic benzoxaborole structure in aqueous solvents. When the resulting 7-substituted benzoxaborole is additionally substituted with an alkyl substituent at position 4 and an aminomethyl substituent at position 3 (numbered using the numbering scheme in Formula I, shown above), such substituted benzoxaboroles are surprisingly selective towards and effective against mycobacteria including M. tuberculosis. The selectivity observed is assessed by comparing MIC values for such compounds relative to inhibition (toxicity) of these compounds to human cells, compared to other substituted benzoxaboroles.
US20090227541 discloses a multitude of compounds, including two tricyclic benzoxaborole compounds with differing antibacterial activity against a panel of Gram negative bacteria (See e.g. Tables 1 and 2), but does not disclose tricyclic benzoxaborole compounds with alkyl substitution at the 4 position on the benzoxaborole ring (numbered using the numbering scheme depicted in Formula I, shown above). WO2012033858 discloses substituted benzoxaboroles with activity against Mycobacterium tuberculosis, including certain substituted benzoxaboroles (see e.g. Examples 1.A through 1.V), but again, no tricyclic benzoxaborole compound is disclosed with an alkyl substitution at the 4 position on the benzoxaborole ring (numbered using the numbering scheme depicted in Formula I, shown above). US2013165411 discloses tricyclic benzoxaborole compounds showing activity against Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli and Klebsiella pneumoniae (see Table 1), but notes specifically that the halogen-substituted tricyclic compounds investigated (Examples 17, 18 and 19) lack activity against A. baumannii, with MIC values ≥16 μg/μL antibacterial activity (see FIG. 1). In addition, nothing in US2013165411 suggests that any of the disclosed tricyclic benzoxaborole compounds are capable of existing as an equilibrium mixture of a tricyclic benzoxaborole structure and a bicyclic benzoxaborole structure in aqueous solvent conditions.